The Multiple Sclerosis Inventory of Cognition for Adolescents (MUSICADO): A brief screening instrument to assess cognitive dysfunction, fatigue and loss of health-related quality of life in pediatric-onset multiple sclerosis.

OBJECTIVE: Screening for cognitive impairment (CI), fatigue and also Health-related quality of life (HRQoL) in patients with pediatric-onset multiple sclerosis (POMS) is of utmost importance in clinical practice. The aim of this study was to establish a new and validated pediatric screening tool "MUSICADO" that is easy to use and time economical. METHODS: 106 patients with POMS aged 12-18 years and 210 healthy controls (HCs) stratified for age and education underwent neuropsychological testing including a screening test "Multiple Sclerosis Inventory of Cognition" for adults and 8 standardized cognitive tests and established scales to assess fatigue and HRQoL. RESULTS: The phonemic verbal fluency task (RWT "s-words"), the Trail Making Test A (TMT-A), and the Digit Span Forward discriminated significantly between patients and HCs (p = 0.000, respectively) and showed the highest proportion of test failure in patients (24.5%, 17.9%; 15.1%, respectively). Therefore, they were put together to form the cognitive part of the "MUSICADO". After applying a scoring algorithm with balanced weighting of the subtests and age and education correction and a cut-off score for impairment, 35.8% of patients were categorized to be cognitively impaired (specificity: 88.6%). Fatigue was detected in 37.1% of the patients (specificity: 94.0%) and loss of HRQoL in 41.8% (specificity 95.7%) with the screening version, respectively. CONCLUSION: The MUSICADO is a newly designed brief and easy to use screening test to help to early identify CI, fatigue, and loss of HRQoL in patients with POMS as cut scores are provided for all three items. Further studies will have to show its usability in independent samples of patients with POMS.

[Effect of two doses of budesonide on exhaled nitric oxide and urinary EPX excretion in asthmatic children]. / Einfluss unterschiedlicher Dosen von Budesonid auf die exhalierte NO-Konzentration und die EPX-Konzentration im Urin bei Kindern mit Asthma bronchiale.

The use of objective outcome measures that assess airway inflammation in pediatric asthma can provide a good evaluation of asthma severity and treatment response. In this double-blind and randomized study the effects of 200 micro g of budesonide and 800 micro g of budesonide on markers of inflammation (exhaled nitric oxide (eNO), eosinophil protein X (EPX) excretion in urine) and on lung function (FEV (1)) were prospectively investigated in 24 ICS-naive children with mild persistent to moderate persistent asthma over a period of eight weeks. After eight weeks of treatment 200 micro g and 800 micro g of budesonide led to a significant decrease (p < 0.025) in eNO [median (90 % interval): 200 micro g: - 17.2 ppb (- 54.6 to 0.9); 800 micro g: - 13.2 ppb (- 44.6 to - 1.7)]. A significant change in urinary EPX excretion was only observed in the high dose group [200 micro g: - 10.3 micro g/mmol creatinine (- 116.2 to 50.5), p = 0.9; 800 micro g: - 49.2 micro g/mmol creatinine (- 231.0 to 48.7), p = 0.02]. However, a significant difference between the change from baseline after 8 weeks of either group was found neither for eNO (p = 0.66) nor for EPX excretion (p = 0.04). In conclusion, our data demonstrate that 800 micro g budesonide per day did not show any advantage in reduction of airway inflammation, measured by eNO and urinary EPX excretion, in children with mild persistent to moderate persistent asthma.

Nasal nitric oxide levels in cystic fibrosis patients are associated with a neuronal NO synthase (NOS1) gene polymorphism.

Nitric oxide (NO) plays an important role in a number of physiological processes in the airways, including host defense. Although the exact cellular and molecular source of the NO formation in airways is unknown, there is recent evidence that neuronal NO synthase (NOS1) contributes significantly to NO in the lower airways of cystic fibrosis (CF) patients. NOS1 protein has been shown to be expressed in nasal epithelium, suggesting an involvement of NOS1-derived NO in upper airway biology. We here hypothesized that nasal NO concentrations in CF patients are related to genotype variants in the NOS1 gene. Measurements of nasal NO concentration and pulmonary function were performed in 40 clinically stable CF patients. Genomic DNA from all patients was screened for an intronic AAT-repeat polymorphism in the NOS1 gene using polymerase chain reaction and simple sequence length polymorphism (SSLP) analysis. The allele size at that locus was significantly (P = 0.001) associated with upper airway NO. Mean (+/- SD) nasal NO concentrations were 40.5 +/- 5.2 ppb in CF patients (n = 12) with high repeat numbers (i.e., both alleles > or =12 repeats) and 72.6 +/- 7.4 ppb in patients (n = 28) with low repeat numbers (i.e., at least one allele <12 repeats). Furthermore, in the group of CF patients harboring NOS1 genotypes associated with low nasal NO, colonization of airways with P. aeruginosa was significantly more frequent than in patients with NOS1 genotypes associated high nasal NO concentrations (P = 0.0022). We conclude that (1) the variability in CF nasal NO levels are related to naturally occurring variants in the NOS1 gene, and (2) that nasal NOS1-derived NO affects the susceptibility of CF airways to infection with P. aeruginosa.

Bronchial hyperresponsiveness to 4.5% hypertonic saline indicates a past history of asthma-like symptoms in children.

SUMMARY. To evaluate the importance of a past history of asthma-like symptoms over a period of 2 years and current bronchial hyperreactivity (BHR), 538 randomly selected schoolchildren, initially aged 7-8 years, were examined. At yearly intervals, three standardized questionnaires, including items from the ISAAC panel, were answered by parents. Following the last questionnaire, BHR to 4.5% hypertonic saline (HS) was recorded. In survey 1, lifetime prevalence of asthma was 4.9%. During the 12-month period, prevalence of wheeze and dyspnea ranged between 9.3 and 5.2% (Survey 1) and 5.9% and 4.4% (Survey 2). Among children with wheeze or dyspnea in Survey 3, BHR (defined as a fall of baseline FEV(1) > or = 15%) was significantly more frequent (50.0% and 60.7%, respectively) than among children without these symptoms (12.8%, P < 0.001, and 12.8%, P < 0.001, respectively). The negative predictive value of BHR to have neither wheeze nor dyspnea was about 88% and did not vary throughout the study (Survey 1, 87%; Survey 2, 88%; Survey 3, 88%). The relative risk of showing BHR was significantly increased in children with wheeze (survey 2, odds ratio (OR) 3.0 (95% confidence interval (CI) 1.0-8.7)) or dyspnea (Survey 1: OR 5.9 (95% CI 1.9-18.5), Survey 3: 5.2 (1.7-16.2), but not in children with dry cough or nocturnal cough (data not shown). Wheeze and dyspnea occurred repeatedly in the same individuals with BHR in a high percentage of children (83.3% and 76.5%, respectively). In conclusion, there is a strong association between recent and previous dyspnea and current BHR, and it indicates intraindividual persistence of symptom history.

Preventive effect of 2 and 10 mg of sodium cromoglycate on exercise-induced bronchoconstriction.

UNLABELLED: This double-blind, randomised and cross-over study was designed to compare the preventive effect against exercise-induced bronchoconstriction (EIB), defined as the percentage decrease in FEV1 > or = 15% after 6 min of exercise, of 2 mg and 10 mg of sodium cromoglycate (SCG), administered through a metered dose inhaler via spacer, in asthmatic children. Each of the 30 subject (age 11.6 +/- 3.2 years) was tested on five occasions. For inclusion, EIB in test1 was required. In tests 2 to 5, all subjects inhaled 2 mg or 10 mg of SCG 20 min and 120 min before exercise in a randomised order. In order to assess excretion of eosinophil protein X (EPX) accompanying EIB, urine samples were collected before and after exercise. The mean percentage fall in FEV1 (+/- SD) in test 1 was 26.8 +/- 9.8%. Inhalation of 2 mg and 10 mg of SCG 20 min before exercise provided a significant preventive effect in 83% and 77% and inhalation 120 min before exercise provided a preventive effect in 63% and 70%, respectively (n = 30). Variance analysis did not reveal a statistically different absolute fall in FEV1 after exercise when both doses (120 min before exercise) were compared (P = 0.356). In an unselected subgroup of 12 children, urinary EPX increased after the challenge without SCG premedication (test 1) (mean change: +48.7 micrograms/mmol creatinine, P = 0.034), whereas no significant increase was found in case of SCG premedication (mean change in microgram/mmol creatinine): 2 mg/20 min: +12.1; 2 mg/120 min: +8.5; 10 mg/20 min: -10.4 and 10 mg/120 min: -23.5; P > 0.1). CONCLUSION: Administration of 10 mg of sodium cromoglycate is no more effective in preventing exercise-induced bronchoconstriction than 2 mg regardless of whether the medication is given 20 or 120 min before exercise. The preventive effect of sodium cromoglycate on exercise-induced bronchoconstriction in asthmatic children is associated with the inhibition of urinary eosinophil protein X excretion.

[Reproducibility in induced sputum in children with asthma]. / Reproduzierbarkeit im induzierten Sputum bei Kindern mit Asthma.

In asthmatic children sputum-induction with hypertonic saline is useful to quantify the eosinophilic inflammation. However, only few data are available about feasibility and safety of the procedure in children. Therefore, taking 9 non-atopic healthy control children (mean age 11.8 years) and 34 asthmatic children (mean age 11.4 years), inhaling n = 25 Budesonid (400-1200 micrograms/die) and n = 9 DNCG (60 mg/die), sputum induction was performed twice within 6 weeks. Briefly, 10 minutes after inhalation of 200 micrograms salbutamol subjects inhaled hypertonic saline (3, 4 and 5%) for in all 30 minutes, while all 5 minutes lung function was checked and expectoration of sputum was supported. Adequate sputum plugs were separated from contaminating saliva and processed immediately employing native chamber and cytospin cell count as well as measurement of eosinophilic cationic protein (ECP). Sputum-induction could be performed in 84 out of 86 planed tests (97.7%) without any objective clinical adverse effects. The mean fall in FEV1 was 3.0%, the maximum 11.0%. The reproducibility of eosinophil, neutrophil and lymphocyte differential cell count (5-95%-values Test1: 0.0-4.2%, 0.8-11.4%, and 3.2-35.1%, respectively) was moderate for eosinophils and neutrophils (Intraclass-Correlation-Coefficient (ICC) 0.41) as well as for lymphocytes (ICC = 0.49). For ECP 5-95%-values Test1: 39.8-8000.0 micrograms/l) only a fair reproducibility (ICC = 0.24) was found. The ICC levels for total cell count (ICC = 0.31) and for weight of the sputum plug (ICC = 0.30) were also fair. Based on the procedure presented induced sputum is a feasible and safe method in childhood. The differential sputum cell count of eosinophils, neutrophils and lymphocytes can be recommended as parameters with moderate reproducibility.

A neuronal NO synthase (NOS1) gene polymorphism is associated with asthma.

Recent family-based studies have revealed evidence for linkage of chromosomal region 12q to both asthma and high total serum immunoglobulin E (IgE) levels. Among the candidate genes in this region for asthma is neuronal nitric oxide synthase (NOS1). We sought a genetic association between a polymorphism in the NOS1 gene and the diagnosis of asthma, using a case-control design. Frequencies for allele 17 and 18 of a CA repeat in exon 29 of the NOS1 gene were significantly different between 490 asthmatic and 350 control subjects. Allele 17 was more common in the asthmatics (0.83 vs 0.76, or 1.49 [95% CI 1.17-1.90], P = 0.013) while allele 18 was less common in the asthmatics (0.06 vs 0.12, or 0.49 [95% CI 0.34-0. 69], P = 0.0004). To confirm these results we genotyped an additional 1131 control subjects and found the frequencies of alleles 17 and 18 to be virtually identical to those ascertained in our original control subjects. Total serum IgE was not associated with any allele of the polymorphism. These findings provide support, from case-control association analysis, for NOS1 as a candidate gene for asthma.

Pulmonary function in children of school age is related to the number of siblings in their family.

It has been suggested that the number of siblings in a family is a surrogate variable for exposure to early infections. Since there may be an association between early respiratory infections and impaired lung function in later life, the aim of this study was to elucidate the relationship between the number of siblings and pulmonary function. We analyzed pulmonary function data from 677 schoolchildren living in 431 nuclear families. Our results show that forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV(1)) expressed as a percentage of deviation from the predicted values (FVC%, FEV(1)%) increase significantly in line with the number of siblings in a family (FVC%: no sibling = reference, 1 sibling = +1.3%, 2 siblings = +1.9%, 3 siblings = +4.0%, 4 or more siblings = +5.1%; P-value for trend = 0.01; FEV(1)%: no sibling = reference, 1 sibling = +1.6%, 2 siblings = +2.0%, 3 siblings = +4.3%, 4 or more siblings = +6.5%; P-value for trend = 0.007). Pulmonary function values were no more strongly related to the number of older siblings than to the number of younger siblings (difference between the trend for older and younger siblings for FCV%: P = 0.7; FEV(1)%: P = 0.9). The association between pulmonary function and number of siblings can be explained neither by the child's atopic status, prevalence of asthma, or history of pneumonia, nor by former or current cigarette smoke exposure. This suggests that pulmonary function status of the child appears to be related to the number of siblings, and is unlikely to be explained solely by exposure to infections early in life. Our data therefore adds strength to the hypothesis that factors which cause the size of a sibship to influence a child's respiratory health have not yet been adequately explained.

Circadian variation of urinary eosinophil protein X in asthmatic and healthy children.

BACKGROUND: It is suggested that urinary eosinophil protein X (EPX) is a noninvasive tool to monitor bronchial inflammation in asthmatic children. However, circadian variation of the number and activation of eosinophils might possibly influence urinary EPX excretion. OBJECTIVE: Measurements of urinary EPX (radioimmunoassay) were used to investigate circadian variation of eosinophilic activation and to monitor bronchial inflammation in children with asthma before and after treatment with corticosteroids. METHODS: Urinary EPX excretion (microg/mmol creatinine) was measured in the morning and afternoon in 22 stable asthmatics and in 16 nonatopic, nonasthmatic controls to investigate circadian variation. Additionally, EPX excretion in the afternoon was analysed in 21 children with chronic asthma before and after 6 weeks of treatment with inhaled corticosteroids, and in seven children within 24 h of admission due to an asthma exacerbation and again 3 months after discharge. RESULTS: EPX excretion in the first morning urine sample of the day compared with the afternoon urine sample was significantly higher both in children with asthma (n = 22; mean +/- standard deviation: 179.7 +/- 97.3 vs 60.9 +/- 40.7 microg/mmol creatinine, P = 0.0001) and in nonatopic nonasthmatic controls (n = 16; 114.5 +/- 57.1 vs 53.4 +/- 29.0 microg/mmol creatinine, P = 0.0001). EPX excretion decreased significantly after 6 weeks of anti-inflammatory treatment in the group of children with chronic asthma (n = 21; 124.7 +/- 84.6 vs 87. 5 +/- 61.9 microg/mmol creatinine, P = 0.02) and in the group of children with an acute asthma exacerbation 3 months after discharge (n = 7; 233.2 +/- 174.5 vs 75.8 +/- 59.5 microg/mmol creatinine, P = 0.02). CONCLUSION: This study suggests a circadian variation of EPX excretion in children with asthma and in nonatopic, nonasthmatic controls. Measurement of EPX excretion is helpful monitoring therapy in asthmatic children if circadian variation is considered.

Comparison between serial skin-prick tests and specific serum immunoglobulin E to mite allergens.

Sensitization to dust mite allergens can be determined by means of a skin-prick test (SPT) or by measurement of specific IgE antibodies in serum (sIgE). In our study, concordance of the results of both methods was analyzed on the basis of reproducible SPT results. Three consecutive SPTs were performed on 138 school children (age 6-8 years) at one-year intervals. SIgE was determined at the end of a two-year observation period. Seven common inhalant allergens (Dpt, Df, birch pollens, hazel pollens, grass pollens and cat and dog dander) were analyzed. The majority of subjects with positive SPT reactions to the respective allergen also showed sIgE (Dpt: 82/86; Df: 53/53; cat dander: 31/32; dog dander: 6/9; birch pollens: 29/31; hazel pollens: 22/22; grass pollens: 37/37). A significant correlation between the SPT [weal diameter (P1) or allergen/ histamine ratio (P2)] and sIgE was found for Dpt (P1 = 0.004/ P2 = 0.016), birch pollens (P1 = 0.002/P2 = 0.0001) and grass pollens (P1 = 0.0005/P2 = 0.0001). There was also a significant correlation between sIgE to Dpt and to either Der p 1 (p = 0.0001) or Der p 2 (p = 0.0001), as well as between sIgE of both major allergens (p = 0.0001). In the analysis of co-sensitization of Dpt and Df, most subjects sensitized to Dpt were also sensitized to Df (57/91). Children with sIgE to Dpt (n = 87) usually showed sIgE to Df(n = 83). In this study, SPT and sIgE results are concordant and appear equivalent when using reproducible SPTs. Therefore, in the case of a positive Dpt result, additional testing for sensitization to Df can be regarded as redundant when Dpt and Df are the major contributors to the allergen content of house dust.

NO in exhaled air is correlated with markers of eosinophilic airway inflammation in corticosteroid-dependent childhood asthma.

The relationship between nitric oxide in exhaled air, levels of sputum eosinophils, sputum eosinophil cationic protein (ECP) and urinary eosinophil protein X (EPX) excretion has not yet been investigated in corticosteroid-dependent childhood asthma. Therefore, taking 25 children with stable asthma (mean age 11.2 yrs) treated with inhaled corticosteroids and nine nonatopic healthy control children (mean age 12.8 yrs) the level of exhaled NO was measured by means of a chemiluminescence analyser before and after sputum induction. This was conducted as a slow vital capacity manoeuvre under standardized conditions with a target flow of 70 mL x s(-1) against a resistance of 100 cm H2O x L(-1) x s. Sputum induction was performed by inhalation of hypertonic saline (3, 4, and 5%) in a standardized manner and a single sample of urine was collected. Exhaled NO (p = 0.01), absolute eosinophil cell counts in sputum (p = 0.02), sputum ECP (p = 0.09) and urinary EPX excretion (p = 0.02) were higher in asthmatics compared to control children. Exhaled NO was positively correlated with sputum ECP (r(s) = 0.59, p = 0.002), urinary EPX (r(s) = 0.42, p = 0.03), and sputum eosinophils (r(s) = 0.30, p = 0.15) in the asthmatic children. These correlations appeared to be pronounced after sputum induction, where NO values had decreased (p = 0.01). None of the correlations were observed in the group of nonatopic control subjects. Additionally there were significant correlations between sputum ECP and sputum eosinophils (r(s) = 0.69, p<0.001) as well as between sputum ECP and urinary EPX excretion (r(s) = 0.58, p = 0.003) in the asthmatics. Exhaled NO provides information about the degree of eosinophilic airway inflammation and thus appears to be a useful and easy-to-perform inflammatory marker in corticosteroid-dependent asthma.

The most common phenotypes of sensitization to inhalant allergens in childhood.

BACKGROUND: Atopic individuals are frequently sensitized to a limited number of certain allergens, although most of them are exposed to multiple inhalant allergens in daily life. OBJECTIVE: We investigated the hypothesis that observed common patterns of sensitization might occur with similar frequency within two independent study populations of school-children. METHODS: The results were derived from skin-prick tests conducted on two large samples of children (study 1: n = 583; study 2: n = 1099) examined with the same panel of six inhalant allergens. RESULTS: In order to ensure that the comparison was uniform, the younger subpopulation of study 1 (n = 147) was compared with the sample of study 2 (n = 374). The highest frequency for monosensitization was found for sensitization to Dermatophagoides pteronyssinus (study 1: 18.4%, study 2: 20.3%), followed by monosensitization to grass pollens (study 1: 12.2%; study 2: 8.8%). Using multiple logistic regression for each specific sensitization, a significantly increased relative risk of sensitization to hazel pollens (study 1 OR 5.9; study 2 OR: 24.3) appeared to be associated with sensitization to birch pollens. The same applied to dog dander (study 1 OR: 7.3; study 2 OR: 2.6), which showed an association with sensitization to cat dander. CONCLUSION: In summary, our data suggest that certain clusters of monosensitization and polysensitization to common inhalant allergens exist among a given population. This may well be a reflection of diversity in disposition to specific sensitization and/or antigen crossreactivity. From a practical point of view the data also might help in counselling parents of allergic children.

Comparison of bronchial challenge with ultrasonic nebulized distilled water and hypertonic saline in children with mild-to-moderate asthma.

There is still controversy about the most suitable method to measure bronchial hyperresponsiveness in children. In epidemiological surveys, nonisotonic aerosols are being used increasingly for bronchial provocation testing. Our aim was to study the acceptability, safety and correlation between two published bronchial challenge tests. Two standardized protocols--the inhalation of hypertonic saline (HS) and ultrasonically-nebulized distilled water (UNDW)--were performed in 36 children: 19 patients with the clinical diagnosis of mild-to-moderate asthma (7-12 yrs of age), and 17 control subjects (8-18 yrs of age). HS challenge involved stepwise inhalation of 4.5% saline (for 0.5, 1, 2, 4 and 8 min), whereas challenge with UNDW was performed as a single step protocol with 10 min inhalation of cold UNDW. Asthma medication was withheld prior to challenge testing. Thirty five subjects completed both challenge tests (one asthmatic patient did not return after UNDW challenge) in random order within a 7 day time interval. For HS a > or = 15% reduction in forced expiratory volume in one second (FEV1) from baseline was considered a positive response, and for UNDW a > or = 10% decrease. In 13 of the 19 asthmatic patients, but in none of the controls, a positive response was observed for UNDW. Fifteen out of 18 patients and one control subject had a positive response to HS. Twelve out of 18 asthmatic children responded to both challenges, three responded only to HS and three had no response to either challenge. There was a negative correlation between log provocative dose causing a 15% reduction in FEV1 (PD15) after HS and the maximum fall in FEV1 after UNDW (rs = -0.63; p < 0.005). The HS challenge had a lower acceptability than challenge with UNDW due to the unpleasant salty taste of HS. However, this did not inhibit the completion of the tests in any subject. The results of this study suggest a good correlation between response to hypertonic saline and ultrasonically-nebulized distilled water in children with mild-to-moderate asthma. A multiple step protocol might be safer when applied in field studies involving children.